DETAILED ACTION
This office action is in response to applicant’s filing dated November 11, 2025.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Claims 1-32 are pending in the instant application. Acknowledgement is made of Applicant's remarks filed November 11, 2025.
Election/Restrictions
Applicant’s election without traverse of Group I, drawn to a compound of formula (I) or a pharmaceutically acceptable salt thereof in the reply filed on November 11, 2025 is acknowledged.
Claim 28, 29, 31, and 32 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on November 11, 2025.
Applicant’s election without traverse of Compound 12:
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as the elected compound species in the reply filed on November 11, 2025 is acknowledged.
The elected compound has been found free of prior art. Thus, examination has been expanded to encompass the scope of compounds of formula (I).
Claims 1-27 and 30 are presently under examination as they relate to the elected compounds of formula (I).
Priority
The present application is a 371 of US Application No. PCT/CN2021/141010 filed on December 24, 2021, which claims benefit of foreign priority to CHINA 202011558776.7, CHINA 202110356037.8, and CHINA 202111419717.6 filed December 25, 2020; April 1, 2021; and November 26, 2021, respectively.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on June 23, 2023 and October 2, 2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement are being considered by the examiner, except where marked with a strikethrough.
Drawings
The drawings are objected to because the 2 bars furthest to the right (dark grey and black) contain text that is difficult to read.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 14, 18, 20, 21, and 23-26 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance:
Claim 14 recites the broad recitation halogen, C1-6 alkyl, and C1-6 alkoxyl, and the claim also recites fluorine, chlorine, methyl, ethyl, methoxyl or ethoxyl which is the narrower statement of the range/limitation.
Claim 18 recites the broad recitation halogen, C1-6 alkyl, and C1-6 alkoxyl, and the claim also recites fluorine, chlorine, methyl, ethyl, methoxyl or ethoxyl which is the narrower statement of the range/limitation.
Claim 20 recites the broad recitation ring A is selected from the group consisting of:
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and the claim also recites ring A is preferably
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which is the narrower statement of the range/limitation.
Claim 21 recites the broad recitation hydrogen, deuterium, halogen, and C1-6 alkyl, and the claim also recites hydrogen, fluorine, chlorine, methyl or ethyl which is the narrower statement of the range/limitation.
Claim 23 recites the broad recitation hydrogen and C1-6 alkyl, and the claim also recites hydrogen, methyl or ethyl, which is the narrower statement of the range/limitation. The claim further recites, more preferably hydrogen, which is narrower statement of the ranges/limitations.
Claim 24 recites the broad recitation R1 is selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, C1-6 alkyl and C1-6 alkoxyl, and the claim also recites preferably R1 is each independently selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl, methoxyl or ethoxyl which is the narrower statement of the range/limitation.
Claim 25 recites the compound of formula (I) is selected from IA-1aa, IA-1ab, IA-2aa, IB-1aa, and IC-1ba, and the claim also recites the compound of formula (I) is preferably IA-1aa-1, IA-1ab-1, IA-2aa-1, IB-1aa-1, and IC-1ba-1 which is the narrower statement of the range/limitation.
Claim 26 recites the compound is the compounds of formula (I) selected from 47 specific compounds, and the claim also recites the compound of formula (I) is preferably selected from 44 specific compounds which is the narrower statement of the range/limitation.
Claim 27 recites An isotopic substituted compound according to claim 1, and the claim also recites the isotopic substituted compound is a deuterated compound which is the narrower statement of the range/limitation.
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim Rejections – Improper Markush Grouping
A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
Claims 1-27 and 30 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
The Markush grouping of compounds represented by the formula recited in Claim 1 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
The Markush grouping is directed to compounds of formula (I) or a pharmaceutically acceptable salt thereof:
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The variables ring A, R1, R2, R3, R4, R5, R6, R7, encompass a myriad of substituents forming heterocycles so diverse, that they will confer the above structure complete different structural and biological properties. Moreover, these variables can be substituted with RA1, RA2, RA3, RA4, RA5 substituents which would confer the above structure with completely different structural and biological properties. For example, Ring A represents a substituted or unsubstituted, 5- to 6-membered aryl ring or heteroaryl ring. With the myriad of compounds that arise from the various definitions and combinations of the variables present in this formula, the result is a group of compounds that include distinct ring systems and a variety of substitution patterns resulting in compounds with no single structural similarity that are not obvious variants of each other. To this end, a comparison of two compounds of the formula (I) presented in claim 26 of the instant specification demonstrates a lack of significant structural similarity and shows compounds of the formula recited in instant Claim 1 are not obvious variants of each other:
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As these compounds demonstrate, the compounds according to the formula (I) include compounds with no common core structure that are not obvious variants of each other. With no significant structural similarity, the Markush grouping is improper.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112(a)
Scope of Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-25, 27, and 30 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a compound of formula (I) wherein m is 0; n is 1; R2 is H;
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is a single bond; R3 is hydrogen; R4 is hydrogen; R5 is methoxy or CHF2; Ring A is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl; R6 and R7 together form a 6-membered ring wherein X2 is -O- or -CR17aR17b-
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R8 and R9 are independently C1-2 alkyl or together form one of the following rings
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does not reasonably provide enablement for the full scope of variables of Ring A, Z, R1, R2, R3, R4, R5, R6, and R7 in the instant claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (1) The breadth of the claims, (2) The nature of the invention, (3) The state of the prior art, (4) The level of one of ordinary skill, (5) The level of predictability in the art, (6) The amount of direction provided by the inventor, (7) The existence of working examples and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Nature of the invention:
The invention is drawn to compounds of the Formula (I) or a pharmaceutically acceptable salt thereof.
Breadth of the invention:
The scope of the claimed invention is very broad, as it is drawn to compounds of the formula:
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allowing for myriad combinations of variables as described in the claims with only a borate moiety in common between the myriad of compounds.
State of the prior art and predictability in the art:
The invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F. 2d 833, 839, 166, USPQ 18, 24 (CCPA 1970).
In terms of the law, MPEP 2107.03 states “evidence of pharmacological or other biological activity of a compound will be relevant to an asserted therapeutic use if there is reasonable correlation between the activity in question and the asserted utility. Cross v. Iizuka, 753 F. 2d 1040, 224 USPQ 739 (Fed. Cir. 1985); In re Jolles, 628 F. 2d 1322, 206 USPQ 885 (CCPA 1980); Nelson v. Bowler, 626 F. 2d 853, 206 USPQ 881 (CCPA 1980).” If correlation is lacking, it cannot be relied upon, Ex parte Powers, 220 USPQ 924; Rey-Bellet and Spiegelberg v. Engelhardt v. Schindler, 181 USPQ 453; Knapp v. Anderson, 177 USPQ 688. Indeed, the correlation must have been established “at the time the tests were performed”, Hoffman v. Klaus, 9 USPQ2d 1657.
Tautermann (Quantum Mechanics in Drug Discover, Humana Press, 2020, Chapter 1, pp. 1-17), cited for evidentiary purposes, teaches drug discovery is a very challenging, cost-intensive, and in terms of investment risky endeavor; on average, it takes 10–15 years and an investment of more than 2.5 billion dollars to get a new drug to the Market; especially the clinical phases cause extremely high costs and late-stage failures, especially in phase II studies, are quite common (page 1, 1st paragraph). Tautermann teaches the largest attrition in clinical phases is observed in phase II studies; the main goal is the assessment of the efficacy of the compound yielding a clinical proof of concept; a recent analysis from four major pharma companies revealed that the cause for attrition in phase II is mainly caused by lack of efficacy followed by safety issues; efficacy for a certain indication is usually preclinically tested in animal models; however, the translatability from animal models to the human situation is not always given; there are several reasons for this; often the disease condition cannot adequately be induced in animals (page 3, last paragraph). Tautermann teaches small molecules have several advantages, such as being cell and brain permeable, the lower cost of goods in their production, and oral administration; however, they are not always the easiest path forward for challenging targets; especially in the case of difficult or so far undruggable targets, new design strategies are required to be successful (page 5, last paragraph). Thus, Tautermann further establishes that the state of the art of drug design is highly unpredictable.
Level of ordinary skill in the art:
An ordinary artisan in the area of drug development would have experience in synthesizing chemical compounds for particular activities. The synthesis of new drug candidates, while complex, is routine in the art. The process of finding new drugs that have in vitro activity against a particular biological target (i.e., receptor, enzyme, etc.) is well known. Additionally, while high throughput screening assays can be employed, developing a therapeutic method, as claimed, prior to synthesizing and testing compounds is generally not well-known or routine, given the complexity of certain biological systems.
The amount of direction provided and working examples:
The compound core depicted with specific substituents represents a narrow subgenus for which applicant has provided sufficient guidance to make and use; however, the disclosure is not sufficient to allow extrapolation of the limited examples to enable the scope of the compounds instantly claimed. Applicant has provided no working examples of any compounds, compositions, or pharmaceutically acceptable salts where R4- was not defined as mentioned above in the present application.
Within the specification, “specific operative embodiments or examples of the invention must be set forth. Examples and description should be of sufficient scope as to justify the scope of the claims. Markush claims must be provided with support in the disclosure for each member of the Markush group. Where the constitution and formula of a chemical compound is stated only as a probability or speculation, the disclosure is not sufficient to support claims identifying the compound by such composition or formula.” See MPEP 608.01(p).
MPEP § 2164.01 (a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here that Applicant is not enabled for making these compounds.
Conclusion
Claims 1-27 and 30 are rejected.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RAYNA B RODRIGUEZ whose telephone number is (571)272-7088. The examiner can normally be reached 8am-5:00pm, Monday - Thursday.
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/Rayna Rodriguez/ Primary Examiner, Art Unit 1628